BIOCHEMICAL EVALUATION OF AMINERGIC FUNCTION DURING RESPONSES TO STRESS & DISEASE

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The main objectives of this project are (1) to determine the physiologic significance of alterations in plasma levels and urinary excretion rates of the catecholamines, their metabolites and their precursor, DOPA; (2) to develop in animals and humans clinically useful methods for assessing catecholaminergic function; and (3) to apply these methods to examine function of catecholaminergic neurons in the peripheral sympathetic nervous system and in brain. Changes in tissue or plasma levels or urinary excretion rates of catecholamines and their metabolites, and tissue tyrosine hydroxylase levels are evaluated, during and after stress, in response to pharmacologic treatments, or in disease states in animals, in normal subjects, and in patients with various neurologic or related disorders (autonomic dysfunction, Parkinson's disease, hypertension, etc). in rats, plasma levels of DOPA parallel pharmacologic or stress-induced enhancement of norepinephrine release, even after adrenalmedullectomy. Tyrosine hydroxylase levels in tissues do not reflect the rate of catecholamine production, indicating that tyrosine hydroxylation can be regulated independently of the levels of tyrosine hydroxylase. Plasma levels of DOPAC, the deamination product of dopamine and HVA, its O-methylated derivative, increase under conditions in which norepinephrine is released. This occurs also in the central nervous system, as indicated by experiments in which microdialysates are obtained from specific nuclei in rat brain hypothalamus. Inhibitors of tyrosine hydroxylase or ganglionic blockade with chlorisondamine prevent stress-induced elevations of DOPA, dopamine and norepinephrine and their metabolites in plasma. Increments in plasma levels of DOPA and DOPAC reflect rates of tyrosine hydroxylation, mostly in peripheral sympathetic neurons. Most patients with pure autonomic failure were found to have low plasma levels of DOPA, norepinephrine, DHPG and DOPAC, consistent with loss of peripheral sympathetic neurons, whereas in most patients with multiple system atrophy, levels of DOPA, DHPG and DOPAC are generally normal; this is consistent with normal catecholamine biosynthesis in these patients who are believed to have intact peripheral sympathetic neurons but diminished nerve impulse traffic from the central nervous system.